HIV persists despite HAART, and discontinuation of HAART typically leads to high virus level rebound. A priority therefore is to identify and ultimately destroy these latently-infected virus reservoirs. To accomplish this, it becomes important to specifically identify the cells and tissue sites that harbor HIV during latency and HAART. Our long-term goal is to inhibit or prevent virus rebound after discontinuation of HAART. The purpose of this R21/R33 proposal is to verify the contributions of CD4+ T cells and macrophages as reservoir cells in SIV- infected, HAART-treated rhesus macaques. Our central hypothesis is that tissue macrophages (in addition to CD4+ T cells) serve as major virus (SIV) reservoirs that develop initially in short-lived macrophages and transi- tion to longer-lived macrophages in deep tissues. The aims of phase I (R21) are: Aim 1. To determine the contribution of CD4+ T cells to the SIV reservoir in SIV-infected macaques undergoing effective HAART. Our working hypothesis is that in vivo depletion of CD4 cells (via anti-CD4 antibody) in SIV-infected macaques undergoing effective HAART will directly demonstrate the proportion of CD4 T cells (vs macrophages) that contribute to the SIV reservoir. Aim 2. To determine the contribution of monocytes/macrophages to the reservoir in SIV-infected macaques undergoing effective HAART. Our working hypothesis is that the in vivo depletion of monocyte /macrophages (via liposome-alendronate) of the SIV-infected macaques undergoing effective HAART will also demonstrate a contribution of macrophages (vs CD4+ T cells) to the SIV reservoir. These studies focus on lung as a model to closely examine T cell and macrophage reservoirs in deep tis- sues. This sets the foundation for the corroborating studies of phase II (R33) to now examine viral reservoirs after discontinuation of HAART (i.e. to determine if viral rebound is prevented by having depleted the viral reservoirs or where viral reservoirs remain if virus rebound occurs). Aim 3. To determine if in vivo depletion of CD4 and/or monocyte/macrophages prevents virus rebound after discontinuation of HAART. Our working hypothesis is that both CD4+ T cells and macrophages con- tribute to SIV reservoirs and that elimination of either or both cell populations followed by discontinuation of HAART will lead to maintenance of low or absent viral load. Conversely, if virus rebound occurs, we will define the remaining or alternate sites of the virus reservoirs that need to be targeted. The overall results will move work forward to developing rational intervention strategies to inhibit progression or cure AIDS in humans.